Identification of a Subset of Trace Amine-Associated Receptors and Ligands As Potential Modulators of Insulin Secretion
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bioRxiv preprint doi: https://doi.org/10.1101/2020.09.10.288951; this version posted September 11, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Coordination of two enhancers drives expression of olfactory trace amine- associated receptors Aimei Fei1,8, Wanqing Wu1,8, Longzhi Tan3,8, Cheng Tang4,8, Zhengrong Xu1, Xiaona Huo4, Hongqiang Bao1, Mark Johnson5, Griffin Hartmann5, Mustafa Talay5, Cheng Yang1, Clemens Riegler6, Kristian Joseph6, Florian Engert6, X. Sunney Xie3, Gilad Barnea5, Stephen D. Liberles7, Hui Yang4, and Qian Li1,2,* 1Center for Brain Science, Shanghai Children's Medical Center, Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; 2Shanghai Research Center for Brain Science and Brain-Inspired Intelligence, Shanghai 201210, China; 3Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA; 4Institute of Neuroscience, State Key Laboratory of Neuroscience, Key Laboratory of Primate Neurobiology, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Research Center for Brain Science and Brian-Inspired Intelligence, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; 5Department of Neuroscience, Division of Biology and Medicine, Brown University, Providence, RI 02912, USA; 6Department of Molecular and Cellular Biology and Center for Brain Science, Harvard University, Cambridge, MA 02138, USA; 7Howard Hughes Medical Institute, Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; 8These authors contributed equally to this work. *Correspondence to [email protected], phone: +86-21-63846590 ext. 776985 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.09.10.288951; this version posted September 11, 2020. -
Is TAAR1 a Potential Therapeutic Target for Immune Dysregulation In
Graduate Physical and Life Sciences PhD Pharmacology Abstract ID# 1081 Is TAAR1 a Potential Therapeutic Target for Immune Dysregulation in Drug Abuse? Fleischer, Lisa M; Tamashunas, Nina and Miller, Gregory M Addiction Sciences Laboratory, Northeastern University, Boston MA 02115 Abstract Discovered in 2001, Trace Amine Associated Receptor 1 (TAAR1) is a direct target of Data and Results amphetamine, methamphetamine and MDMA. It is expressed in the brain reward circuity and modulates dopamine transporter function and dopamine neuron firing rates. Newly-developed compounds that specifically target TAAR1 have recently been investigated in animal models In addition to brain, TAAR1 is expressed in immune cells METH promotes PKA and PKC Phosphorylation through TAAR1 as candidate therapeutics for methamphetamine, cocaine and alcohol abuse. These studies • We treated HEK/TAAR1 cells and HEK293 involving classic behavioral measures of drug response, as well as drug self-administration, Rhesus and Human cells with vehicle or METH, with and without strongly implicate TAAR1 as a potential therapeutic target for the treatment of addiction. In activators and inhibitors of PKA and PKC. addition to its central actions, we demonstrated that TAAR1 is upregulated in peripheral blood Cells Lines mononuclear cells (PBMC) and B cells following immune activation, and that subsequent • We performed Western blotting experiments to activation of TAAR1 by methamphetamine stimulates cAMP, similar to the function of measure levels of phospho-PKA and phospho- adenosine A2 receptors which are also present in immune cells and play a critical role in the PKC. immune response. Here, we are investigating the relationship between TAAR1 and the • We found that specific activators of PKA and adenosine A2 receptor at the level of cellular signaling and receptor dimerization. -
TRAR4 (TAAR6) (NM 175067) Human Tagged ORF Clone Lentiviral Particle Product Data
OriGene Technologies, Inc. 9620 Medical Center Drive, Ste 200 Rockville, MD 20850, US Phone: +1-888-267-4436 [email protected] EU: [email protected] CN: [email protected] Product datasheet for RC220756L3V TRAR4 (TAAR6) (NM_175067) Human Tagged ORF Clone Lentiviral Particle Product data: Product Type: Lentiviral Particles Product Name: TRAR4 (TAAR6) (NM_175067) Human Tagged ORF Clone Lentiviral Particle Symbol: TAAR6 Synonyms: TA4; taR-4; taR-6; TAR4; TAR6; TRAR4 Vector: pLenti-C-Myc-DDK-P2A-Puro (PS100092) ACCN: NM_175067 ORF Size: 1035 bp ORF Nucleotide The ORF insert of this clone is exactly the same as(RC220756). Sequence: OTI Disclaimer: The molecular sequence of this clone aligns with the gene accession number as a point of reference only. However, individual transcript sequences of the same gene can differ through naturally occurring variations (e.g. polymorphisms), each with its own valid existence. This clone is substantially in agreement with the reference, but a complete review of all prevailing variants is recommended prior to use. More info OTI Annotation: This clone was engineered to express the complete ORF with an expression tag. Expression varies depending on the nature of the gene. RefSeq: NM_175067.1, NP_778237.1 RefSeq Size: 1038 bp RefSeq ORF: 1038 bp Locus ID: 319100 UniProt ID: Q96RI8 Protein Families: Druggable Genome, GPCR, Transmembrane Protein Pathways: Neuroactive ligand-receptor interaction MW: 38.3 kDa Gene Summary: This gene encodes a seven-transmembrane G-protein-coupled receptor that likely functions as a receptor for endogenous trace amines. Mutations in this gene may be associated with schizophrenia.[provided by RefSeq, Feb 2010] This product is to be used for laboratory only. -
Jenna K. Caines, Sherri L. Christian, Mark D. Berry Department of Biochemistry, Memorial University of Newfoundland, St. John'
Trace Amine-Associated Receptors in Monocytes: A Constant Low-Level Expression Jenna K. Caines, Sherri L. Christian, Mark D. Berry Department of Biochemistry, Memorial University of Newfoundland, St. John’s NL Trace amine-associated receptors (TAARs) Is TAAR1 differentially expressed in response to Pro- and Are any TAARs differentially expressed between § G protein-coupled receptors anti-inflammatory stimuli? monocyte and macrophage lineages? § Established throughout the body in vertebrates Table 1: Datasets with n ≥ 3 examining human and mice macrophages Table 2: Datasets with n ≥ 3 containing several monocyte and § Humans have 6 functional isoforms: TAAR1, TAAR2, TAAR5, TAAR6, TAAR8, and TAAR9 treated with pro- and anti-inflammatory stimuli macrophage lineages from mice TAARs and the immune system Dataset Treatment Time TAAR1 p-value Dataset Cell type Number of lineages Treatment § Found in leukocyte populations1 GSE53986 Untreated (control) 0h examined INFγ 24h 0.8 GSE15907 Lung Macrophage 2 NA 1 § TAAR1 suspected of regulating immune response GSE60290 Untreated (control) 0h Peritoneal Macrophage 6 NA § Potential target for pharmacological treatment of immune disorders2 INFγ 18h 0.3 Spleen Macrophage NA GSE43075 Untreated (control) 0h Blood Monocyte 2 NA Hypothesis LPS 4h 0.45 Mesenteric LN monocyte 1 NA GSE121646 Untreated (control) 0h Oral Salmonella § TAAR1 will show differential expression upon activation and LPS 8h 0.7 Small intestine macrophage 2 Typhimurium(72 h) GSE19315 Untreated (control) 0h between leukocyte populations -
Discovery of Novel Imidazolines and Imidazoles As Selective TAAR1
Discovery of Novel Imidazolines and Imidazoles as Selective TAAR1 Partial Agonists for the Treatment of Psychiatric Disorders Giuseppe Cecere, pRED, Discovery Chemistry F. Hoffmann-La Roche AG, Basel, Switzerland Biological Rationale Trace amines are known for four decades Trace Amines - phenylethylamine p- tyramine p- octopamine tryptamine (PEA) Biogenic Amines dopamine norepinephrine serotonin ( DA) (NE) (5-HT) • Structurally related to classical biogenic amine neurotransmitters (DA, NE, 5-HT) • Co-localised & released with biogenic amines in same cells and vesicles • Low concentrations in CNS, rapidly catabolized by monoamine oxidase (MAO) • Dysregulation linked to psychiatric disorders such as schizophrenia & 2 depression Trace Amines Metabolism 3 Biological Rationale Trace Amine-Associated Receptors (TAARs) p-Tyramine extracellular TAAR1 Discrete family of GPCR’s Subtypes TAAR1-TAAR9 known intracellular Gs Structural similarity with the rhodopsin and adrenergic receptor superfamily adenylate Activation of the TAAR1 cyclase receptor leads to cAMP elevation of intracellular cAMP levels • First discovered in 2001 (Borowsky & Bunzow); characterised and classified at Roche in 2004 • Trace amines are endogenous ligands of TAAR1 • TAAR1 is expressed throughout the limbic and monoaminergic system in the brain Borowsky, B. et al., PNAS 2001, 98, 8966; Bunzow, J. R. et al., Mol. Pharmacol. 2001, 60, 1181. Lindemann L, Hoener MC, Trends Pharmacol Sci 2005, 26, 274. 4 Biological Rationale Electrical activity of dopaminergic neurons + p-tyramine -
Characterization of Dopaminergic System in the Striatum of Young Adult Park2-/- Knockout Rats
www.nature.com/scientificreports OPEN Characterization of Dopaminergic System in the Striatum of Young Adult Park2−/− Knockout Rats Received: 27 June 2016 Jickssa M. Gemechu1,2, Akhil Sharma1, Dongyue Yu1,3, Yuran Xie1,4, Olivia M. Merkel 1,5 & Accepted: 20 November 2017 Anna Moszczynska 1 Published: xx xx xxxx Mutations in parkin gene (Park2) are linked to early-onset autosomal recessive Parkinson’s disease (PD) and young-onset sporadic PD. Park2 knockout (PKO) rodents; however, do not display neurodegeneration of the nigrostriatal pathway, suggesting age-dependent compensatory changes. Our goal was to examine dopaminergic (DAergic) system in the striatum of 2 month-old PKO rats in order to characterize compensatory mechanisms that may have occurred within the system. The striata form wild type (WT) and PKO Long Evans male rats were assessed for the levels of DAergic markers, for monoamine oxidase (MAO) A and B activities and levels, and for the levels of their respective preferred substrates, serotonin (5-HT) and ß-phenylethylamine (ß-PEA). The PKO rats displayed lower activities of MAOs and higher levels of ß-PEA in the striatum than their WT counterparts. Decreased levels of ß-PEA receptor, trace amine-associated receptor 1 (TAAR-1), and postsynaptic DA D2 (D2L) receptor accompanied these alterations. Drug-naive PKO rats displayed normal locomotor activity; however, they displayed decreased locomotor response to a low dose of psychostimulant methamphetamine, suggesting altered DAergic neurotransmission in the striatum when challenged with an indirect agonist. Altogether, our fndings suggest that 2 month-old PKO male rats have altered DAergic and trace aminergic signaling. -
G Protein-Coupled Receptors
S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2015/16: G protein-coupled receptors. British Journal of Pharmacology (2015) 172, 5744–5869 THE CONCISE GUIDE TO PHARMACOLOGY 2015/16: G protein-coupled receptors Stephen PH Alexander1, Anthony P Davenport2, Eamonn Kelly3, Neil Marrion3, John A Peters4, Helen E Benson5, Elena Faccenda5, Adam J Pawson5, Joanna L Sharman5, Christopher Southan5, Jamie A Davies5 and CGTP Collaborators 1School of Biomedical Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK, 2Clinical Pharmacology Unit, University of Cambridge, Cambridge, CB2 0QQ, UK, 3School of Physiology and Pharmacology, University of Bristol, Bristol, BS8 1TD, UK, 4Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK, 5Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/ 10.1111/bph.13348/full. G protein-coupled receptors are one of the eight major pharmacological targets into which the Guide is divided, with the others being: ligand-gated ion channels, voltage-gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. -
Involvement of the Sigma-1 Receptor in Methamphetamine-Mediated Changes to Astrocyte Structure and Function" (2020)
University of Kentucky UKnowledge Theses and Dissertations--Medical Sciences Medical Sciences 2020 Involvement of the Sigma-1 Receptor in Methamphetamine- Mediated Changes to Astrocyte Structure and Function Richik Neogi University of Kentucky, [email protected] Author ORCID Identifier: https://orcid.org/0000-0002-8716-8812 Digital Object Identifier: https://doi.org/10.13023/etd.2020.363 Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Recommended Citation Neogi, Richik, "Involvement of the Sigma-1 Receptor in Methamphetamine-Mediated Changes to Astrocyte Structure and Function" (2020). Theses and Dissertations--Medical Sciences. 12. https://uknowledge.uky.edu/medsci_etds/12 This Master's Thesis is brought to you for free and open access by the Medical Sciences at UKnowledge. It has been accepted for inclusion in Theses and Dissertations--Medical Sciences by an authorized administrator of UKnowledge. For more information, please contact [email protected]. STUDENT AGREEMENT: I represent that my thesis or dissertation and abstract are my original work. Proper attribution has been given to all outside sources. I understand that I am solely responsible for obtaining any needed copyright permissions. I have obtained needed written permission statement(s) from the owner(s) of each third-party copyrighted matter to be included in my work, allowing electronic distribution (if such use is not permitted by the fair use doctrine) which will be submitted to UKnowledge as Additional File. I hereby grant to The University of Kentucky and its agents the irrevocable, non-exclusive, and royalty-free license to archive and make accessible my work in whole or in part in all forms of media, now or hereafter known. -
The Genetics of Bipolar Disorder
Molecular Psychiatry (2008) 13, 742–771 & 2008 Nature Publishing Group All rights reserved 1359-4184/08 $30.00 www.nature.com/mp FEATURE REVIEW The genetics of bipolar disorder: genome ‘hot regions,’ genes, new potential candidates and future directions A Serretti and L Mandelli Institute of Psychiatry, University of Bologna, Bologna, Italy Bipolar disorder (BP) is a complex disorder caused by a number of liability genes interacting with the environment. In recent years, a large number of linkage and association studies have been conducted producing an extremely large number of findings often not replicated or partially replicated. Further, results from linkage and association studies are not always easily comparable. Unfortunately, at present a comprehensive coverage of available evidence is still lacking. In the present paper, we summarized results obtained from both linkage and association studies in BP. Further, we indicated new potential interesting genes, located in genome ‘hot regions’ for BP and being expressed in the brain. We reviewed published studies on the subject till December 2007. We precisely localized regions where positive linkage has been found, by the NCBI Map viewer (http://www.ncbi.nlm.nih.gov/mapview/); further, we identified genes located in interesting areas and expressed in the brain, by the Entrez gene, Unigene databases (http://www.ncbi.nlm.nih.gov/entrez/) and Human Protein Reference Database (http://www.hprd.org); these genes could be of interest in future investigations. The review of association studies gave interesting results, as a number of genes seem to be definitively involved in BP, such as SLC6A4, TPH2, DRD4, SLC6A3, DAOA, DTNBP1, NRG1, DISC1 and BDNF. -
Receptor Interaction Profiles of 4-Alkoxy-Substituted 2,5-Dimethoxyphenethylamines and Related Amphetamines
ORIGINAL RESEARCH published: 28 November 2019 doi: 10.3389/fphar.2019.01423 Receptor Interaction Profiles of 4-Alkoxy-Substituted 2,5-Dimethoxyphenethylamines and Related Amphetamines Karolina E. Kolaczynska 1, Dino Luethi 1,2, Daniel Trachsel 3, Marius C. Hoener 4 and Matthias E. Liechti 1* 1 Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland, 2 Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, Vienna, Austria, 3 ReseaChem GmbH, Burgdorf, Switzerland, 4 Neuroscience Research, pRED, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland Background: 2,4,5-Trimethoxyamphetamine (TMA-2) is a potent psychedelic compound. Structurally related 4-alkyloxy-substituted 2,5-dimethoxyamphetamines and phenethylamine congeners (2C-O derivatives) have been described but their pharmacology Edited by: is mostly undefined. Therefore, we examined receptor binding and activation profiles of M. Foster Olive, these derivatives at monoamine receptors and transporters. Arizona State University, United States Methods: Receptor binding affinities were determined at the serotonergic 5-HT1A, 5-HT2A, Reviewed by: Luc Maroteaux, and 5-HT2C receptors, trace amine-associated receptor 1 (TAAR1), adrenergic α1 and INSERM U839 Institut du Fer à α2 receptors, dopaminergic D2 receptor, and at monoamine transporters, using target- Moulin, France Simon D. Brandt, transfected cells. Additionally, activation of 5-HT2A and 5-HT2B receptors and TAAR1 was Liverpool John Moores University, determined. Furthermore, we assessed monoamine transporter inhibition. United Kingdom Results: Both the phenethylamine and amphetamine derivatives (Ki = 8–1700 nM and *Correspondence: Matthias E. Liechti 61–4400 nM, respectively) bound with moderate to high affinities to the 5-HT2A receptor [email protected] with preference over the 5-HT1A and 5-HT2C receptors (5-HT2A/5-HT1A = 1.4–333 and Specialty section: 5-HT2A/5-HT2C = 2.1–14, respectively). -
Case–Control Association Study of 59 Candidate Genes Reveals the DRD2
Journal of Human Genetics (2009) 54, 98–107 & 2009 The Japan Society of Human Genetics All rights reserved 1434-5161/09 $32.00 www.nature.com/jhg ORIGINAL ARTICLE Case–control association study of 59 candidate genes reveals the DRD2 SNP rs6277 (C957T) as the only susceptibility factor for schizophrenia in the Bulgarian population Elitza T Betcheva1, Taisei Mushiroda2, Atsushi Takahashi3, Michiaki Kubo4, Sena K Karachanak5, Irina T Zaharieva5, Radoslava V Vazharova5, Ivanka I Dimova5, Vihra K Milanova6, Todor Tolev7, George Kirov8, Michael J Owen8, Michael C O’Donovan8, Naoyuki Kamatani3, Yusuke Nakamura1,9 and Draga I Toncheva5 The development of molecular psychiatry in the last few decades identified a number of candidate genes that could be associated with schizophrenia. A great number of studies often result with controversial and non-conclusive outputs. However, it was determined that each of the implicated candidates would independently have a minor effect on the susceptibility to that disease. Herein we report results from our replication study for association using 255 Bulgarian patients with schizophrenia and schizoaffective disorder and 556 Bulgarian healthy controls. We have selected from the literatures 202 single nucleotide polymorphisms (SNPs) in 59 candidate genes, which previously were implicated in disease susceptibility, and we have genotyped them. Of the 183 SNPs successfully genotyped, only 1 SNP, rs6277 (C957T) in the DRD2 gene (P¼0.0010, odds ratio¼1.76), was considered to be significantly associated with schizophrenia after the replication study using independent sample sets. Our findings support one of the most widely considered hypotheses for schizophrenia etiology, the dopaminergic hypothesis. -
The Involvement of Trace Amine-Associated Receptor 1 and Thyroid Hormone Transporters in Non-Classical Pathways of the Thyroid Gland Auto-Regulation
The Involvement of Trace Amine-Associated Receptor 1 and Thyroid Hormone Transporters in Non-Classical Pathways of the Thyroid Gland Auto-Regulation by Maria Qatato a Thesis submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Cell Biology Approved Dissertation Committee Prof. Dr. Klaudia Brix Jacobs University Bremen Prof. Sebastian Springer, DPhil Jacobs University Bremen Dr. Georg Homuth Ernst-Moritz-Arndt-Universität Greifswald Date of Defence: 16 January 2018 Department of Life Sciences and Chemistry Statutory Declaration Family Name, Given/First Name Qatato, Maria Matriculation number 20330110 What kind of thesis are you submitting: PhD Thesis English: Declaration of Authorship I hereby declare that the thesis submitted was created and written solely by myself without any external support. Any sources, direct or indirect, are marked as such. I am aware of the fact that the contents of the thesis in digital form may be revised with regard to usage of unauthorized aid as well as whether the whole or parts of it may be identified as plagiarism. I do agree my work to be entered into a database for it to be compared with existing sources, where it will remain in order to enable further comparisons with future theses. This does not grant any rights of reproduction and usage, however. This document was neither presented to any other examination board nor has it been published. German: Erklärung der Autorenschaft (Urheberschaft) Ich erkläre hiermit, dass die vorliegende Arbeit ohne fremde Hilfe ausschließlich von mir erstellt und geschrieben worden ist. Jedwede verwendeten Quellen, direkter oder indirekter Art, sind als solche kenntlich gemacht worden.